16-1218222-G-A

Variant names:

• chr16-1218222-G-A
• rs768988866
• NM_021098.3:c.5458G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_021098.3(CACNA1H):​c.5458G>A​(p.Glu1820Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000968 in 1,549,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.71
• Publications: 2 publications found

Genes affected

CACNA1H (HGNC:1395): (calcium voltage-gated channel subunit alpha1 H) This gene encodes a T-type member of the alpha-1 subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. The alpha-1 subunit has 24 transmembrane segments and forms the pore through which ions pass into the cell. There are multiple isoforms of each of the proteins in the complex, either encoded by different genes or the result of alternative splicing of transcripts. Alternate transcriptional splice variants, encoding different isoforms, have been characterized for the gene described here. Studies suggest certain mutations in this gene lead to childhood absence epilepsy (CAE). [provided by RefSeq, Jul 2008]

CACNA1H Gene-Disease associations (from GenCC):

• hyperaldosteronism, familial, type IV

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• childhood absence epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• epilepsy, childhood absence, susceptibility to, 6

  Inheritance: AD Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021098.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.5458G>A	p.Glu1820Lys	missense	Exon 33 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.5440G>A	p.Glu1814Lys	missense	Exon 32 of 34	NP_001005407.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.5458G>A	p.Glu1820Lys	missense	Exon 33 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.5473G>A	p.Glu1825Lys	missense	Exon 32 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.5476G>A	p.Glu1826Lys	missense	Exon 32 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152222 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000647 AC: 1 AN: 154454 AF XY: 0.0000122

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000167

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000859 AC: 12 AN: 1397234 Hom.: 0 Cov.: 32 AF XY: 0.0000102 AC XY: 7 AN XY: 689080

African (AFR) AF: 0.00 AC: 0 AN: 31586

American (AMR) AF: 0.00 AC: 0 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 35728

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5442

European-Non Finnish (NFE) AF: 0.00000834 AC: 9 AN: 1078656

Other (OTH) AF: 0.0000345 AC: 2 AN: 57972

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152222 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

African (AFR) AF: 0.0000482 AC: 2 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000115 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Uncertain:1

Jun 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1H protein function. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1820 of the CACNA1H protein (p.Glu1820Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. ClinVar contains an entry for this variant (Variation ID: 579650).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.86	L
PhyloP100		9.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.61		Gain of methylation at E1820 (P = 0.0024)
MVP		0.94
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.63
gMVP		0.83
Mutation Taster		=45/55	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs768988866; hg19: chr16-1268222;